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Virology > Lecture 15 - Innate Immunity and Viral Immune Evasion > Flashcards

Lecture 15 - Innate Immunity and Viral Immune Evasion Flashcards

1
Q

How long does it take for the innate immune system to be activated?

A

Fewer than 24 hours

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2
Q

Three types of PRRs

A

Toll-like receptors
Rig-like receptors
Nod-like receptors

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3
Q

Transcription factors activated by TLRs and RLRs

A

Interferon-releasing factor (IRFs)
AP-1
NFkB

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4
Q

Transcription factors activated when NLR detects PAMPs

A

AP-1

NFkB

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5
Q

NOD-like receptors that detect PAMPS

A

NOD1

NOD2

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6
Q

NLR that detects PAMPs, DAMPs, changes in cytosolic ionic milieu

A

NLRP3

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7
Q

What is activated when nod-like receptors detect DAMPS or cytoplasmic DNA?

A

Caspase-1 inflammasome

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8
Q

TLRs that detect viruses

A

TLR3
TLR7
TLR8
TLR9

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9
Q

Where are all TLRs that detect viruses located?

A

In the endosome

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10
Q

TLR3 ligand

A

dsRNA

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11
Q

TLR7 ligand

A

ssRNA

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12
Q

TLR8 ligand

A

ssRNA

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13
Q

TLR9 ligand

A

CpG unmethylated dinucleotides

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14
Q

How are TLRs activated?

A

Ligand induces dimerisation

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15
Q

TLR3 signal transduction pathway
1)
2)
3)

A

1) TRIF adaptor molecule
2) IRF3 and IRF7 lead to type 1 interferon release
3) NFkB leads to pro-inflammatory cytokine release

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16
Q

TLR8 signal transduction pathway

A

1) MyD88 adaptor molecule

2) NFkB leads to pro-inflammatory cytokine release

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17
Q

TLR7 and TLR9 signal transduction pathway

A

1) MyD88 adaptor molecule

2) IRF7 leads to type 1 interferon release

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18
Q 
IRF3 effects
1)
2)
3)
4)
A

1) Acts as a transcription factor.
2) Stimulates type 1 interferon production.
3) Promotes ISG56 production.
4) Interacts with transcription factor eLF-3, leading to inhibition of protein synthesis.

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19
Q

Important rig-like receptors

A

RIG-I, MDA5

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20
Q

RIG-1, MDA5 location

A

Cytoplasmic

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21
Q

What is the adaptor molecule for RIG-1 and MDA5, and where is it located?

A

IPS-1, and located on the mitochondrial membrane (a MAV, mitochondrial-associated antiviral protein)

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22
Q

What does RIG-I recognise?

A

Short dsRNA.

5’ triphosphate on ssRNA. Cellular mRNA has a cap, so doesn’t have triphosphorylated 5’ end

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23
Q

MDA5 ligand

A

Long dsRNA

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24
Q

Examples of viruses detected by RIG-I

A

Influenza (orthomyxoviridae).
Vesicular stomatitis (rhabdoviridae)
Hep C, West Nile virus, dengue (flaviviridae)
Rotavirus (reoviridae)

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25
Q

Examples of viruses detected by MDA5

A

Encephalomyocarditis virus (EMCV) (picronaviridae)
Rotavirus (reoviridae)
West Nile virus, dengue (flaviviridae)

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26
Q

What are RIG-I and MDA5?

A

RNA helicases

27
Q

What happens when RIG-I or MDA5 bind ligand?

A

Dimerisation, interaction with MAVS.

Interaction with MAVS facilitated via the CARD domain

28
Q

What does activation of MAVS induce?

A

IRF pathway: Phosphorylation of IRF3 and IRF7 via stimulation of TRAF3 and TDK1.

NFkB pathway: MAVS interaction with TRAF6, RIP1 and FADD leads to NFkB activation.

29
Q 
Cytosolic PRRs that detect DNA
1)
2)
3)
4)
5)
A

1) TLR9
2) DAI
3) IFI16
4) AIM2
5) DHX9, DHX36

30
Q

Example of a virus that releases DNA into cytoplasm

A

Poxviruses

31
Q

Can viruses activated inflammasomes?

A

Yes.

32
Q

Global actions of interferons

A

1) Brain - Induces IL-1, IL-6, TNFa, which lead to fever, fatigue, sleep
2) Induces CSFs, which lead to haematopoiesis, lymphocyte mobilisation
3) Liver - Induces IL-1, IL-6, TNFa, lead to acute phase protein production

33
Q

Type 1 interferones

A

IFNa, IFNb

34
Q 
Type 1 interferon signalling cascade
1)
2)
3)
4)
A

1) IFNa/b binds to IFNa/b receptor on cel surface
2) Tyk2, Jak1 are phosphorylated
3) This leads to phosphorylation, dimerisation of STAT1, STAT2.
3) STAT1/2 dimer enters nucleus, joins with p48
4) STAT1/2/p48 trimer binds to ISRE (IFN stimulated response element)

35
Q

Type 2 interferons

A

IFNg

36
Q 
Type 2 interferon signalling cascade
1)
2)
3)
4)
A

1) IFNg binds to IFNg receptor on cell surface
2) Jak1, jak2 are phosphorylated.
3) This leads to phosphorylation, dimerisation of STAT1.
4) STAT1 homodimer enters nucleus, binds to GAS (gamma activation site)

37
Q

Are interferon stimulated response element genes produced at any time except during viral infection?

A

No

38
Q 
Examples of IFN-induced proteins
1)
2)
3)
4)
A

1) MxA
2) OAS
3) RNase L
4) Protein kinase R (PKR)

39
Q 
MxA protein
1)
2)
3)
4)
A

1) Found only in the cytoplasm
2) Recognises, sequesters viral nucleocapsid in bundles.
3) Used as a marker of infection (only present in virus-infected cells)
4) Very effective against influenza

40
Q

OAS and RNase L role

A

Detects and cleaves viral RNA species

41
Q 
OAS and RNase L mode of action
1)
2)
3)
4)
5)
A

1) Viral RNA detected, ISRE stimulated, OAS transcribed
2) OAS monomer forms a tetramer.
3) OAS tetramer makes 2’-5’-adenylic acid (nucleotide).
4) 2’5’-adenylic acid induces RNase L monomers to dimerise, making RNase L active.
5) Active RNase L degrades viral RNA

42
Q

Which nucleotide does OAS tetramer make?

A

2’-5’-adenylic acid

43
Q

What induces dimerisation of RNase L monomers?

A

2’-5’-adenylic acid

44
Q

Antiviral protein that shuts down host cell protein translation

A

Protein kinase R

45
Q

Protein kinase R mode of action
1)
2)
3)

A

1) Inactive PKR has a dsRNA binding domain
2) If inactive PKR binds to dsRNA, PKR is phosphorylated, dimerises, is activated
3) Active PKR phosphorylates host transcription factor elF2a, shutting down host translation

46
Q

How do poxviruses subvert host antiviral response?

A

Inactivate adaptor molecules of TLRs, so that they can’t initiate signal transduction

47
Q

Viruses that alter TLR adaptor molecules to subvert host antiviral response

A

Poxviruses, hep C

48
Q

Way that influenza can subvert host antiviral response

A

Makes ‘fake’ dsRNA that can bind to receptor (RLR, TLR3), bit can’t initiate downstream activity

49
Q 
Ways that viruses can subvert host antiviral response
1)
2)
3)
4)
5)
6)
A

1) Inactivate TLR adaptor molecules
2) Make ‘fake’ dsRNA that can bind to receptor, but can’t initiate downstream activity (influenza)
3) Interfere with helicase activation (poliovirus)
4) Interfere with MAVS signalling (Hep C)
5) Prevent activation of transcription factors (rabiesvirus)
6) Prevent MHCI presentation

50
Q

Example of a virus that interferes with helicase activaiton

A

Poliovirus

51
Q

Example of a virus that interferes with MAVS signalling

A

Hep C

52
Q

Example of a virus that prevents activation of transcription factors

A

Rabiesvirus

53
Q 
Viruses that interfere with IFN signalling 
1)
2)
3) 
4)
A

1) West Nile virus
2) SARS coronavirus
3) Measles
4) Mumps

54
Q

How does West Nile virus interfere with IFN signalling?

A

Prevents phosphorylation of Jak1 and Tyk2.

Redistributes cholesterol from the cell membrane, which disables IFN receptor

55
Q

How does SARS CoV interfere with IFN signalling?

A

Prevents nuclear import of phosphorylated STAT1/STAT2 dimer

56
Q

How do measles and mumps interfere with IFN signalling?

A

Prevent nuclear import of phosphorylated STAT1/STAT2 dimer

57
Q

ADAR1 (p150)
1)
2)
3)

A

1) Detects dsRNA
2) Edits RNA by changing A to I
3) Results in destruction of RNA secondary structures, prevents RNA coding for anything

58
Q

Antiviral protein that edits viral RNA

A

ADAR1 (p150)

59
Q

Human immune effector proteins that detect dsRNA
1)
2)
3)

A

1) OAS/RNase L
2) PKR
3) ADAR1

60
Q

Is it common for viruses to interfere with PKR function?

A

Yes. Almost every virus has a strategy for PKR interference

61
Q

Examples of viruses that interfere with PKR by producing fake RNAs

A

HIV, adenoviruses, EBV

62
Q

Example of a virus that interferes with PKR by degrading it

A

Poliovirus

63
Q

Examples of viruses that interfere with PKR by preventing phosphorylation or dimerisation

A

Poxviruses

Reoviruses

64
Q

Examples of viruses that itnerfere with PKR function by preventing phosphorylation of elF2a

A

Poxviruses
Hep C
Herpes simplex

Virology (29 decks)

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